DK160561B - ANALOGY PROCEDURE FOR THE PREPARATION OF 3-AMINOCHRANE-5 END DERIVATIVES OR SALTS THEREOF - Google Patents

Description

- 1 -

DK 160561 B

The invention relates to an analogous process for the preparation of novel 3-amino enriched-5-end derivatives or their addition salts with inorganic or organic acids and of the general formula I as set forth in the preamble of claim 1.

In the general formula I and hereinafter, the term represents alkyl of 1 to 5 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl, the term hydroxyalkyl having 2-5 carbon atoms represents e.g. hydroxyethyl or hydroxypropyl. The term acyl derived from a carboxylic acid having 3-8 carbon atoms denotes e.g. propionyl, n-butyryl or isobutyryl, the term alkoxycarbonyl of 2-8 carbon atoms denotes e.g. methoxy, ethoxy or propoxycarbonyl. The residue derived from an alpha-amino acid may e.g. is selected from Ala, Val, Leu, Ile, Asp, Asn,

Glu, Gin, Ser, Thr, Cys, Met, Lys, Arg, Phe, Tyr, Trp, His,

Pro, Nva, Nle, Hyp and Orn, these amino acids being in D or L form, as well as Sar and Gly. When denoting a group derived from a peptide having 2-3 alpha amino acids, these are selected e.g. among the alpha amino acids above.

When the alpha amino acids or peptides are N-mono- or dialkylated, it is preferably methyl, ethyl or propyl.

25

It is conventionally determined that the symbols of the alpha amino acids represent these acids in their D or L configuration (for example, the term Ala alanine denotes in D or L form).

30

The nomenclature used is according to IUPAC, whose rules are mainly published in Biochem. J. (1972) 1926, 773-780.

The addition salts with the inorganic or organic acids may e.g. be the salts formed with hydrochloric acid, hydrogen bromide acid, nitric acid, sulfuric acid, phosphoric acid,

DK 160561 B

acetic acid, formic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkanesulfonic acids such as methane or ethanesulfonic acid, arylsulfonic acids such as benzene or p-toluenesulfonic acids and aryl carboxylic acids.

In particular, among the compounds obtained by the process of the invention are mentioned the derivatives of formula I and their acid addition salts with inorganic or organic acids, wherein the amino group is in the 3alpha position, represents a hydrogen atom and R2 represents an acyl group derived from an acyl group. alpha-amino acid or a peptide having 2-3 amino acids.

Among these, mention should be made in particular of the derivatives of formula I wherein X represents CH, CH-j

In 3 or | 3 -C = O -CH / wOH

wherein the hydroxide is in the 20alpha position, and in particular 20alpha-methyl ammopregn-5-en-20-one and the other compounds prepared in the examples.

The value of the compounds prepared by the process of the invention is demonstrated by the rosette test by comparing the compounds of Examples 1, 2, 3 and 4 below with 3alpha-amine enumeration-5-en-20-one hydrochloride (Compound A).

A. Rosette test on red blood cells from sheep 3 0

Administration to animals of a compound capable of stimulating the immune system leads to an increase in their ability to respond to an injection of an immunogenic substance.

3-month-old male rats are sensitized by intraperitoneal injection of sheep erythrocytes on day 0; 7 days after the spleen is removed and the splenocytes are contacted with ferry erythrocytes. The percentage of splenocytes, about 35

DK 160561 B

- 3 - which erythrocytes form a rosette is determined. The test compounds are administered orally daily from day -1 to day 1, and the immunostimulatory dose is the dose of the compound that doubles the percentage of rosettes observed in relation to control animals. The results are shown in Table I.

Table I

Example No. Dose in mq / kg 10 12 2 1 3 2 4 5. c Compound A inactive at 5

1 O

B. Acute toxicity

The acute toxicity is determined by oral administration of the test compounds to mice, and the maximum dose, which does not cause any 2q mortality after 8 days, is determined (LDq). The results are shown in Table II.

Table II

Example No. LD 2 in mg / kq 1 200 2 400 3 400 4 600 30

Compound A 200

The results of Table I show that the compounds of the invention have good immunostimulatory activity.

Conversely, 3-amino-pregn-5-one-20-one has no effect at the 5 mg / kg maximum dose investigated.

DK 160561 B

- 4 -

The process according to the invention is characterized by the characterizing part of claim 1.

Under preferred conditions for initiating the process of the invention, proceed as follows: a) The reaction of the amine of formula II with the halide of formula III is carried out in the presence of an acid-binding agent, especially a hydroxide, a carbonate, a bicarbonate or an alkali metal acetate (e.g., sodium or potassium acetate), an alkaline earth metal carbonate (e.g., calcium carbonate), a tertiary amine (e.g., trialkylamine or pyridine), or an alkali metal alcoholate (e.g., sodium ethylate). For example, the turnover can be is carried out in inert solvents or suspension media such as dioxane, dimethylformamide, benzene, toluene or a halogenated hydrocarbon such as methylene chloride.

b) The reaction of the amine of formula II with an acid of formula III1 is carried out with an activating agent such as a carbodiimide. Other techniques may be used, e.g. the one according to "The Peptides", vol. 1, Academic Press 1979.

c) The reaction of the amine of formula II or of the compound of formula I which represents a hydrogen atom and represents hydroxylalkyl, with the alpha amino acid or peptide, the amino group of which is monosubstituted, disubstituted or protected with a readily cleavable protecting group, takes place in the presence of a condensing agent. In this case, the condensing agent has the purpose of activating the acid group in the amino acid.

As a condensing agent, a carbodiimide of the formula 35 can be used A1-N = C = N-B1 where A ^ and represents an alkyl group of 1-8 carbon atoms, optionally bearing a dialkylamino group, or

DK 160561 B

- a cycloalkyl group.

In particular, mention may be made of dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, preferably the latter.

5

A 2-chloro-N-methylpyrinium halide such as the iodide can also be used.

An alkyl chloroformate such as e.g.

With methyl, ethyl or isobutyl chloroformate. An alkyl pyrophosphite such as e.g. ethylpyrophos-phosphite.

As a readily cleavable protecting group, preferably benzyloxycarbonyl (Z) or tert-butyloxycarbonyl (BOC) may be used.

For elimination of the above-readily cleavable protecting group, preferably an acid such as hydrochloric acid is used as a decomposing agent. You work, for example. by an alcoholic solution of hydrogen chloride or by anhydrous hydrogen chloride by bubbling in nitromethane.

Acids such as p-toluenesulfonic acid, formic acid or trifluoroacetic acid may also be used. Hydrogen can also be used in the presence of palladium, e.g. for removing the protecting group Z.

d) The reaction of the amine of formula II with the methyl or hydroxyalkyl halide takes place in the presence of the same acid-binding agents and solvents as in the case of the reaction with the halide of formula III.

e) The reaction of the compound of formula I, which represents a hydrogen atom, represents a hydroxyalkyl group 35 having 2-5 carbon atoms, and X and the wavelength have the same meaning as above, with the halide of formula IV being carried out

DK 160561 B

- 6 - according to the character of R '' '' under the conditions described above in connection with the reaction of the amine of formula II with the halide of formula III.

The derivatives of formula I have a basic character with the exception of those wherein R 2 represents acyl or alkyloxycarbonyl.

Advantageously, the addition salts of the derivatives of formula I can be prepared by reacting in practically stoichiometric amounts of an inorganic or organic acid 10 with the derivative of formula I. The salts can be prepared without isolation of the corresponding bases.

The compounds prepared by the process of the invention have very interesting pharmacological properties.

In particular, they have remarkable immunotherapeutic properties. They are particularly suitable for stimulating immunoreactions.

These properties are shown below in the Experimental Part 20.

These properties justify the use of the 3-amine enrichment - 5-end derivatives as well as their pharmaceutically acceptable salts as drugs.

25

In particular, among the drugs are those constituted by the novel 3-amino enumerator-5s of the general formula I, wherein the amino group is in the 3alpha position, hydrogen and R2 represents a group derived from an alpha-30 amino acid or of a peptide having 2-3 amino acids, as well as their addition salts with acceptable acids for pharmaceutical purposes.

Among them, in particular, are those of formula I, where X 35 represents the group

DK 160561 B

- 7 - CH, CH-,

| 3 or | 3 -C = O -CH OH

wherein the hydroxyl group is in the 20alpha position, as well as their addition salts with pharmaceutically acceptable acids.

5

In particular, among the latter are the following: 2-amino-N- (20-oxopregn-5-en-3alpha-yl) -acetamide, (2S) -2-amino-N- (20-oxopregn-5-en-3alpha- yl) -propionamide and 10-3alpha-methylaminopregn-5-ene-20-one as well as their addition salts with pharmacologically acceptable acids.

These drugs find e.g. use for the treatment of immunodeficiency and in particular autoimmune diseases resulting from a deficiency in certain lymphocytes, whether in non-specific diseases of the connective tissue of an organ such as e.g. rheumatoid arthritis, erythematous systemic lupus, or specific diseases of an organ such as thyroiditis, pemphigus or hemolytic anemia.

The compounds prepared by the method of the invention can be used as adjuvant therapy in the antibiotic therapy and in the anti-cancerous chemotherapy.

25

The normal dose, which varies according to the derivative used, the patient being treated and the disorder in question, may e.g. be from 10 mg to 1 g per day. per day by oral route in humans of the derivative of Example 4 as an antibiotherapeutic adjuvant.

Thus, the derivatives of formula I and their addition salts with inorganic or organic acids can be used to prepare pharmaceutical preparations containing the 35 derivatives or salts as active ingredient.

DK 160561 B

- 8 -

Thus, the derivatives of formula I and their addition salts with inorganic or organic acids can be used to prepare pharmaceutical compositions containing the subject derivatives or salts as active ingredient.

5

As drugs, the derivatives of the general formula I and their addition salts with pharmaceutically acceptable acids can be incorporated into pharmaceutical compositions intended for administration by the digestive or parenteral route.

10

The pharmaceutical compositions may e.g. be solid or liquid and are present in the pharmaceutical forms commonly used in human medicine, e.g. tablets, sugary tablets, gelatine capsules, granules, suppositories and 15 injection preparations. They are manufactured according to the usual methods. The active ingredient or ingredients are incorporated therein together with additives commonly used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, fats, animal or plant origin, paraffin derivatives, glycols and various moisturizers. -, dispersing or emulsifying agents and preservatives.

The starting compounds of formula II wherein X represents a group CH0

-CH OH

can be manufactured as follows: 30

A compound of formula V is reduced

- 9 -

DK 160561 B

wherein the wave line has the same meaning as above, by e.g. an alkali metal such as sodium in a solvent such as a low molecular weight aliphatic alcohol such as ethanol to give a compound of formula 10 2 wherein the wavy line has the same meaning as above, in the form of a mixture of 20alpha and 20beta isomers which is separated, f. eg. by preparing the trifluoroacetyl derivative of the amine and the alcohol, then chromatographing and hydrolyzing the trifluoroacetyl groups of the separated isomers.

An example of such a preparation is shown below in the experimental section.

20

The amino acids or peptides, whose amine group is mono- or disubstituted, can be prepared by classical amine alkylation processes.

The following examples illustrate the process of the invention.

30 35

DK 160561 B

- 10 -

Example 1,

The hydrochloride of 3'-methylaminopregn-5-en-20 ~ one.

Step A: (20-Oxopregn-5-en-5a-yl) -carbamic acid ethyl ester.

6 g of 3α-aminopregn-5-ene-20-one (holamine) 5 are dissolved in 100 ml of methylene chloride, 22 ml of 1 K sodium hydroxide solution are added at 5-10 ° C and then in 10 minutes 2 ml of ethyl chloroformate and stirred for 1 hour. hour"

Acidify with 15 ml 2 of hydrochloric acid, decant, wash the organic phase with water, dry and evaporate 10 to dryness. The residue obtained is taken up in 70 ml of ethyl ether, heated to reflux, suctioned, washed with ether, dried and 6.25 g of the expected compound. Mp, 202 ° C.

Step Bi (20 «20-ethylenedioxypregn-5-en-3a-yl) -carbamine, acid-ethyl ester.

You heat to approx. 50 ° C under inert atmosphere 10.9 g of the substance obtained in the previous step with 54.5 ml of ethylene glycol and 22 ml of ethyl orthoformate. 220 mg of monohydrated p-toluenesulfonic acid is added and stirred for approx. 3 to 20 March. Cool to 20 ° G, add 4.2 ml of triethylamine, pour with stirring on 550 ml of water, suction, wash with water, dry at 60 ° C and obtain 12 g of the expected compound. Mp. ca. 200 ° C,

Step C: 5α-methylaminopregn-5-ene-20-one (U-methylholamine) 25 and its hydrochloride.

1.145 g of lithium aluminum hydride in 110 ml of tetrahydrofuran are suspended under inert atmosphere and 6.51 g of the compound obtained in the previous step dissolved in 65 ml of tetrahydrofuran are refluxed during J> 0 minutes. After refluxing for 1 hour 5 minutes bring to 15-20 ° C, gently add 15 ml of water and then 15 ml of concentrated hydrochloric acid and stir for 1 hour 45 minutes. Alkaline with 25 ml of potassium hydroxide and 5 ml of concentrated ammonia water, stir for 10 minutes, 35 ml of 100 ml of seignette salt solution, decant, extract with ethyl acetate, wash with saturated brine, dry, evaporate to dryness under reduced pressure, recrystallize from ethyl acetate and give 4, 07 g of the expected

DK 160561 B

- 11 - compound * Snip, approx. 139 ° C,

Hydrochloride formation.

Dissolve 1.5 g of base in 50 ml of ethyl acetate at 25-5 0 ° C, add an excess of hydrogen chloride dissolved in ethyl acetate, ice cool, suction, wash with ethyl acetate, dry at 40 ° C under reduced pressure, recrystallize from ethanol to obtain 1.31 g of the expected compound,

Mp. about 270 ° C.

Analysis: ^ 22 ^ 36 ^^ 0- = 365.99 Calculated: C fo 72.20 Efo 9.91 W ° 3.83 Cl $ 9.69 Found: 72.4 10.1 3.8 9.7

Example 2,

Fumarate of 2-amino-N-meth: [1- N- (20-oxopregn-5-ene-3g-yl) -15-acetamide,

Step A: 2- (((Phenylmethoxyl) carbonyl) amino) -N- ((20-oxo) - P regn-5-en-5a-yl) -N-methyl thylamide .

4.43 g of the base of Example 1 are dissolved in 130 ml of chloroform and 27 ml of triethyl-20 amine, 5.6 g of N- (benzyloxycarbonyl) -glycine (Z-glycine) is added and over 20 ml. Minutes with stirring 3.89 g of 2-chloro-N-methylp2 / ridinium iodide. 1 hour later, 800 mg of the pyridinium salt above is added, stirring for 20 minutes, adding another 400 mg of pyridinium salt, stirring another 25 for 20 minutes, washing with 1N hydrochloric acid and with 1N sodium hydroxide and with water, drying, evaporating to dryness, purifying by chromatography on silica gel (eluent: methylene chloride and ethyl acetate (9: 1)), recrystallizes from ethyl acetate to give 5.8 g of the expected compound, 30 Mp, 130 ° C and then 150 ° C,

Step B: 2-Amino-Hf-methyl-W- (20-oxopregn-5-en-3o: -yl) -acetamide and its fumarate.

Under inert atmosphere, 6.2 g of the compound obtained in step A is dissolved in 60 ml of tetrahydrofuran, 35 g of 1.2 g of coal with 5% palladium is added and hydrogen is bubbled through. After 2 hours, the catalyst is filtered, the catalyst is washed with methylene chloride, evaporated to dryness to give 4.55 g of the expected mixture as.

DK 160561 B

- 12 - resin.

Formation of fumarate.

1.9 g of the above base are dissolved in ethanol in 4 ml of 95 $ ethanol, a hot solution of 560 mg of fu-5 guaric acid in 6 ml of 95 $ ethanol is added, crystallization is initiated, ice-cooled for 1 hour, suction , washes with ice-cold ethanol, dries at 60 ° C under vacuum to obtain 2.02 g of the expected compound in the form of hemihydrate. Mp.ca, 160 ° C. Analysis: H2 ° = 511 »63 10 Calculated: C $ 65.73 H1 ° 8.67 TS & 5.47 Found: 65.6 8.5 5.4

Example 5 (2S) -2-Amino-H- (20-oxopregn-5-en-5a-yl) -propionamide and its hydrochloride.

Step A: 2- ((1,1-Dimethylethoxy) -oarbonyl) -amino-3β- (20-oxo-pre-5-ene-3alpha-yl) -propionamide 3.15 g of -amine and 2.08 g of tert.-butyloxycarbonyl-L-alanine (BOC-1 · -20 alanine) in 75 ml of chloroform and 15 ml of pyridine, add 2.1 g of hydrohloride of 1-ethyl-3- (3-dimethylaminopropyl) ) - carbodiimide and stir for 1 hour 15 minutes. Wash with 2N hydrochloric acid and with aqueous sodium bicarbonate solution, dry, distill to dryness under reduced pressure, purify by ohromatography on silica gel (eluent: benzene and methyl ethyl ketone (1: 1)) to obtain 4.5 g of the expected compound in oily form .

Step B: Hydrochloride of (2S) -2-amino-N- (20-oxopregn-5-ene-3alpha-yl) -propionamide Stir for 2 hours 30 minutes under inert atmosphere 4.5 g of that of Step A obtained compound in solution in 30 µl of 2 S dry hydrogen chloride in methanol. Distill to dryness under reduced pressure at 30 ° C, crystallize 30 ml of ethyl acetate, suction, dissolve 35 in 15 ml of refluxing methanol, filter, add 50 ml of ethyl acetate, evaporate to half volume, suction dry, dry at 40 ° G. under reduced pressure to obtain 2.5 g of the expected compound, m.p. 260 ° C.

DK 160561 B

- 13 -

Analysis! C24H39C1N2 ° 2 = 423.03 calculated: C # 68.14 H1 ° 9.29 N # 6.62 Cl # 8.38 found: 68.4 9.3 6.5 8.5 5 Example 4

Hydrochloride of 2-amino-IT- (20-oxopregn-5-en-3a-yl) -acetamide

Working according to a method analogous to that described above in Example 2, and reacting Z-glycine or ir- (benzyloxycarbonyl) -glycine with holamine, produces the expected compound.

Mp. 295 ° C after crystallization of ethyl acetate.

Analysis: C₂ ^H ^ gN₂O HC, HCl = 409.019 Calc'd: C # 67.54 H # 9.12 Cl # 8.67 N # 6.85 Found: 67.8 9.1 8.5 6.7

Example 5

Fumarate of (2S) -2-amino-1- (29-oxopregn-5-en-3a-yl) -1H-indole-3-propanamide.

By working according to a method analogous to Example 3 by reacting BOC-I-tryptophan with holamine, the expected compound is prepared. Mp. 180 ° C after crystallization of methanol.

Analysis: C32H45N3O2, H00C-CH = CH-C00H, CH2 OH = 617.76 Calc'd: C # 68.39 H # 7.91 N # 6.47 Found: 68.1 8.0 6.5

Example 6

Hydrochloride of 2-amino-N - ((20S) -20-hydroxypregn-5-ene-3a-30-yl) -acetamide.

Working according to a method analogous to that described above in Example 2 by reacting Z-glycine with (20S) -3a-aminopregn-5-en-20-ol, the expected compound is prepared. Mp. 264 ° C (dec.) After crystallization of ethyl acetate.

Analysis: C23H38rW2O2, HCl = 447.495 Calc'd: C # 67.20 H # 9.56 Cl # 8.63 B # 6.82 Found: 67.3 9.6 8.7 6.8 "14 -

DK 160561 B

(20S) -3a-aminopregn-5-en-20-ol used as starting compound can be prepared as follows: frins 1: 3a-aminopregn-5-en-20-ol.

Reflux 100 ml of propanol, reflux over 20 minutes and at the same time add 5 g of sodium in small portions and a solution of 5 g of holamine in 5 ml of propanol and maintain the reflux. After 1 hour 25 minutes, allow to re-enter room temperature, ice cool, acidify with acetic acid to a pH of 6, return to 10 to ρΗ value of 8 using potassium carbonate, dilute with 500 ml of water, evaporate partially, record in 300 water, crystallize for 24 hours in a refrigerator, filter, rinse the crystals with water, dissolve in 10 ml of methylene chloride, add 50 ml of ethyl acetate and 30 ml of isopropyl ether, evaporate the methylene chloride, crystallize for 16 hours in a refrigerator and obtain 3 g of the expected connection. Mp. 160 ° C.

Step 2: (203) - (3- (trifluoroethylamino) - pregn-5-ene-20-yl) trifluoroacetate.

Dissolve 5.5 g of the above compound in 55 ml of methylene chloride, add 5.5 ml of pyridine, bring to 0 ° C, add 5.5 ml of trifluoroacetic anhydride over 5 minutes, stir at room temperature for 15 minutes, evaporate to dryness , absorbs in cyclohexane, filters, evaporates to dryness, chromatographs the residue on silica gel (eluent: cyclohexane and ethyl acetate (9: 1)) and obtains 3 fractions, the first corresponding to the (20R) isomer, the second (3, 56 g) for a mixture of (20R) and (20S), and the third (1.5g) for the desired (20S) isomer, m.p. 140 ° 0th

Step 3: (2OS) -3a-Aminopregn-5-en-20-ol.

An ice-bath suspension of 2.4 g of the above obtained compound was added in 24 ml of methanol, 12 ml of 2 L sodium hydroxide solution added, stirred for 2 hours 30 minutes at room temperature, diluted with water, extracted with methylene chloride, washed with phase with saturated brine, dries, evaporates and gets 1.42 g of the expected base, m.p. 190 0.

DK 160561 B

- 15 -

Example 7

Tablets are prepared according to the prescription: - hydrochloride of 2-amino-H- (20-oxopregn-5 * -en--3a-yl) -acetamide 20 mg 5 - additive to form 1 tablet of 100 mg (details of additive: lactose, starch, talc, magnesium stearate),

Pharmacological study, 10 1 · Adjuvant for anaphylactic shock »

Principle.

The administration to animals of a substance which is capable of stimulating the activity of the immune systems is demonstrated by an increase in shock in response to the administration of an antigen to which the animal is sensitized.

Male mice of 30-35 g are sensitized by intraplantar route with bovine serum albumin. 8 days later, they receive this antigen by intravenous route. Under the conditions of minimal sensitization, the control animals did not exhibit a fatal shock at this last administration.

The compound to be tested is injected by intra-plant route mixed with the antigen: If this compound is adjuvant, it will increase sensitization and a fatal shock will occur upon administration by intravenous route.

As an active dose, the dose that causes a mortality rate of over or above $ 50 of the animals is determined.

results:

Compound of Example Dose per animal in mg 30 4 1 6 4 2. Rosette test on sheep red blood cells,

Principle,

Administration to animals of a compound capable of stimulating the activity of the immune systems is shown by increasing their ability to respond by injecting an immunogenic substance.

DK 160561 B

- 16 -

Male females at 3 months are sensitized by intraperitoneal route with sheep erythrocytes (day 0). 7 days later (day 7), their spleens are removed and the splenocytes are contacted with sheep erythrocytes. The percentage of leucocytes is then counted. around which the erythrocytes 5 have formed rosettes.

The compound to be tested is administered orally daily from day -1 to day 1,

The immunostimulatory dose is considered to be the dose of the compound which approximately doubles the percentage of rosettes observed compared to control animals.

Results.

Compound of Example Dose per animal in mg / kg per us 3 2 15 4 5 3. Acute toxicity study.

The non-lethal doses (DLq) of various investigated compounds are evaluated after oral administration in mice. 20 DLq is the maximum dose that does not produce any 8-day mortality.

The results obtained are as follows:

Compound of Example DD 2 in mg / kg 3 over 400 25 4 600 6 over 400 30 35

Claims (7)

An analogous process for the preparation of 3-amino enrichment - 5-end derivatives or their addition salts with inorganic or organic acids and of the general formula I 'sXtSf ... Ϊ, where X represents a group CH0 CH0 I3 or | 3 -C = O -CH OH with the wavy lines indicating that the group in question is in alpha or beta position, R R represents a hydrogen atom or a hydroxyalkyl group having 2-5 carbon atoms, R2 represents a hydrogen atom, a hydroxyalkyl group having 2-5 carbon atoms, aliphatic acyl derived from a carboxylic acid 2q of 3-8 carbon atoms or alkoxycarbonyl of 2-8 carbon atoms or an acyl group derived from an alpha amino acid or a peptide having 2-3 amino acids, wherein the amine group is either free or mono- or disubstituted with an alkyl group having 1-5 carbon atoms, however, and R 2 does not at the same time represent a hydrogen atom, and if the amino group is in the 3-beta position, then I) when X represents a group -COCH do not at the same time represent a hydroxyethyl group, and II) when X represents a group -CH 2 O 2 CH 2, and R 2 represents a 2q hydrogen atom, R 2 is not an ethoxycarbonyl group, or of the general formula I above, where X represents the group CH -C = 0 35 - 18 - DK 160561 B represents e a hydrogen atom or an acyl group derived from an alpha amino acid, R 5 represents a methyl group and the amino group is in the 3alpha position, characterized by reacting an amine of formula II rt5 meaning as above, - either with a halide of formula III Hal-R'2 (III) wherein Hal represents chloro, bromo or iodo, and R4 represents an aliphatic acyl group derived from a carboxylic acid of 3-8 carbon atoms or alkoxycarbonyl of 2 -8 carbon atoms, to give a compound of formula I wherein R 1 represents a hydrogen atom, R 2 represents a group R 1 defined as above, and X and the wavelength have the same meaning as above which compound of formula I is desired if isolated -20 is converted to an addition salt with an inorganic or organic acid, - or with an acid or anhydride of formula III 'AO-R' '2 (III1) where A represents a hydrogen atom or a group R' r ,, 2 kete9ner an aliphatic acyl group derived from one carboxylic acid with 3 to 8 carbon atoms to give a compound of formula I wherein R 1 represents a hydrogen atom, R 2 represents r 2, as defined above, and X and the wavelength have the same meaning as above, which compound I desired isolates and converts to an addition salt with an inorganic or organic acid, or with an alpha amino acid or peptide having 2-3 amino acids, wherein the amine group is monosubstituted or di-substituted with an alkyl group having 1-5 carbon atoms or protected with a group which is readily decomposable, especially by acid hydrolysis or hydrogenolysis, and then it is treated to remove the protecting group to obtain a compound of formula I wherein a hydrogen atom represents R2 represents an acyl group derived from an alpha-amino acid or a peptide having 2-3 alpha-amino acids, wherein the amino group is free or mono- or disubstituted with an alkyl group of 1-5 carbon atoms, and X and the wavelength have 5 sec. breastfeeding meaning as above, which if desired is isolated and converted to an addition salt with an inorganic or organic acid, or with a hydroxyalkyl halide of 2-5 carbon atoms and wherein the halogen is chlorine, bromine or iodine to give a compound of the formula Wherein the amine at the 3-position is mono- or disubstituted with a hydroxylalkyl group having 2-5 carbon atoms and X and the wavelength have the same meaning as above, which compound of formula I is either isolated and converted to an addition salt with an inorganic or organic acid, if desired, or, in the case where R 2 represents a hydrogen atom, react with a halide of the formula IV Hal-R '"2 (IV) 20 where r 1, 2 represents a hydroxyalkyl group having 2-5 carbon atoms , aliphatic acyl derived from a carboxylic acid of 3-8 carbon atoms or alkoxycarbonyl of 2-8 carbon atoms, and Hal has the same meaning as above to give a compound of formula I wherein R 1 represents a hydroxyalkyl 25 y 1 group having 2-5 carbon atoms, R 2 represents a group R 4 defined as above, and X and the wavelength have the same meaning as above, which is isolated and converted to an addition salt with an inorganic or organic acid, if desired, or also in the case where R 2 represents a hydrogen atom, the compound of formula I is reacted with an alpha amino acid or a peptide having 2-3 amino acids, the amino group of which is monosubstituted or disubstituted by an alkyl group of 1-5 carbon atoms or protected by a group which is readily decomposable, especially by acid hydrolysis or by hydrogenolysis, and then treated to remove the protecting group to give a compound of formula X wherein represents a hydroxyalkyl group of 2- Represents an acyl group derived from an alpha amino acid or a peptide having 2 or 3 alpha amino acids, wherein the amino group is free or mono- or disubstituted with an alkyl group having 1-5 carbon atoms, and X and the wavelength have the same meaning as above, which is isolated and converted to an addition salt with an inorganic or organic acid, if desired, - or, in the case where X represents a group -COCH And wherein the amino group is in the 3alpha position, with a methyl halide or also ethyl chloroformate, followed by reduction under intermediate protection of the 20-oxo group to give a compound of formula I wherein X represents a group -COCH represents a hydrogen atom, R 2 represents a methyl group, and the amino group is in the 3alpha position, which compound is isolated and optionally converted to an acid addition salt or reacted with an alpha amino acid whose amino group is intermediate. protected, to give a compound of formula I wherein X represents a group 20 -COCH 3, R 4 represents an acyl group derived from an alpha amino acid, R is converted into an acid addition salt. Process according to claim 1, characterized in that X represents a group CH CH I or | -C = O -CH OH 30 with the wavy lines indicating that the corresponding groups are in alpha or beta position, R ^ represents a hydrogen atom or a hydroxyalkyl group having 2-5 carbon atoms, R2 represents a hydrogen atom, a hydroxyalkyl group having 2-5 carbon atoms, an aliphatic acyl group derived from a carboxylic acid of 3-8 carbon atoms, or an alkoxycarbonyl group of 2-8 carbon atoms, or an acyl group derived from an alpha-amino acid or a peptide having 2-3 amino acids wherein amine-DK 160561 B - 21 the group is either free or mono- or disubstituted with an alkyl group of 1-5 carbon atoms, however, R 1 and R 2 cannot simultaneously represent a hydrogen atom and, if the amino group is in the 3-beta position, then 5 ) when X represents a group -COCH and R 2 does not at the same time represent a hydroxyethyl group, and II) when X represents a group -CH 2 OH 2 CH 2, and R 1 represents a hydrogen atom, R 2 is not an ethoxycarbonyl group. A process according to claim 1, characterized in that X represents the group -COCH 2, R 2 represents a hydrogen atom, R 2 represents a methyl group and the amino group is in the 3alpha position. Process according to claim 2, characterized in that a compound of formula II, wherein the amino group is in the 3alpha position, is reacted with an alpha-amino acid or a peptide having 2-3 amino acids, wherein the amine group is either intermediately protected or mono-protected. or disubstituted with an alkyl group having from 1 to 5 carbon atoms to give a compound of formula I wherein the amino group is in the 3alpha position, R 1 represents a hydrogen atom and R 2 represents an acyl group derived from an alpha amino acid or a peptide having 2-3 amino acids, wherein the amino group is either free or mono- or disubstituted with an alkyl group having 1-5 carbon atoms. Method according to claim 4, characterized in that X represents a group 30 CEL OH .. I or | -C = O -CH OH where the hydroxyl group is in the 20alpha position. The process according to claim 2, characterized by reacting a compound of formula II wherein X represents a group -CO-CH 3 and the amino group is in the 3-alpha-N-position, with N- (benzyloxycarbonyl) glycine. Process according to claim 2, characterized in that a compound of formula II is reacted wherein X 5 represents a group -COCH 2 and the amino group is in the 3alpha position, with tert-butyloxycarbonyl-L-alanine. 10 15 20 25 30 35